PROJECT SUMMARY: Bacterial pneumonia continues to be an important comorbidity in HIV- infected patients even though anti- retrovial therapy has succeded in restoring CD4 cell counts. HIV patients demonstrate increased microbial colonization of the lower airways and the microbial flora is similar to that observed in diseases with impaired mucociliary clearance (MCC) like cystic fibrosis and COPD. HIV patients demonstrate impaired nasal mucociliary clearance. Since the physiological mechanisms regulating nasal MCC is similar to tracheobronchial MCC it is possible that HIV suppresses this as well. The three principal components of the MCC apparatus are, a mucus layer, ciliary beating and a periciliary airway surface liquid layer that facilitates ciliary beating. cystic fibrosis transmembrane conductance regulator (CFTR) plays a pivotal role in regulating the pericilary airway surface liquid. Our preliminary data show that HIV protiens Tat and gp120 can suppress components of the MCC apparatus. HIV Tat and cigarette smoke suppress CFTR biogenesis and function via a common pathway involving TGF-? signaling. Moreover, HIV Tat and cigarette smoke synergize to cause an additive suppression of CFTR function. Suppression of CFTR mRNA is not due to transcriptional suppression and strongly posits a role for miRNA mediated post-transcriptional gene silencing. HIV gp120 and cigarette smoke suppress baseline ciliary beating. This is significant since 60% of HIV patients also smoke tobacco. Beta-2-adrenergic receptor agonists primarily used as bronchodilators can restore ciliary beating and CFTR function (if CFTR availabiltiy can be restored) thereby restoring MCC. Based on these observations, Aim 1 will elucidate the role of miRNA mediated gene silencing in CFTR suppression by TGF-beta and identify the miRNAs involved. Aim 2 will confirm that HIV patients demonstrate decreased CFTR biogenesis and this is possibly due to increased TGF-?1 levels. We will also confirm that HIV patients demonstrate suppressed ciliary beating and this can be restored by ?2-agonists that are routinely prescribed as bronchodilators in airway diseases like asthma and COPD. Together, these aims will examine basic molecular mechanisms relating to increased bacterial pneumonia in HIV patients while simultaneously testing therapeutic approaches to restore components of the MCC apparatus in these patients. The proposal aims will address one of the major basic research scientific gaps identified by the Working group namely, ?Interplay of HIV, inflammation, ART, co-infections, and traditional risk factors in the progression of HIV-related HLB diseases?, for RFA-HL-14-029, and identify therapeutic leads to restore MCC and decrease the incidence of bacterial pneumonia in HIV patients.